One hundred three cases of nodular sclerosis (NS) and mixed-cellularity Hodgkin's disease were evaluated for expression of bcl-2 oncogene protein, because previous studies have revealed expression of bcl-2 in these subtypes but only rarely in the nodular lymphocyte-predominance subtype. Reed-Sternberg (RS) cells and lacunar variants were positive for bcl-2 in 51 of 86 NS cases and 4 of 17 mixed-cellularity cases. In individual cases of NS, the percentage of RS cells and lacunar variants positive for bcl-2 ranged from minimal (in 5 cases) to 100% positive (mean, 34%). By univariate analysis, expression of the bcl-2 gene product in RS cells was observed in a significantly greater proportion of NS Hodgkin's disease cases than MC cases (P < .009), a finding that may have implications on the pathogenesis of this disorder.